Periodic Reporting for period 1 - MITOQUAD (Unveiling the mitochondrial role of DNA2, a human helicase-nuclease causing mtDNA deletion associated syndrome.)
Période du rapport: 2018-01-01 au 2019-12-31
Mitochondria are key organelles as they are responsible for supplying the proper form of energy necessary to the cell to exert all its functions. Conversely to other cellular compartments, they possess their own DNA (mtDNA). The genes encoded by this small genome are essential for the function of the mitochondria. Multiple deletions in mtDNA give rise to a variety of neuromuscular symptoms, associated with genetic inherited disorders and aging. Moreover, mtDNA deletions have been reported in patients with neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. In spite of its medical importance, not much is yet known about the mechanisms by which mtDNA deletions are formed. Recently, in silico and in vitro analyses reveal that mtDNA deletion breakpoints occur preferentially at specific secondary DNA structures called G-quadruplexes (GQs). GQs are nucleic acid sequences rich in guanines that can assemble into a four-strand structures. mtDNA is enriched in sequences with the potential to form GQs, but their occurrence in vivo, as well as their function and implication on mtDNA replication, are still under debate. In the nuclear DNA (nDNA), GQs are involved in the regulation of different biological processes such as replication, transcription and telomere maintenance and their dynamic is modulated by several proteins. Among them, the nuclease-helicase DNA2 has been shown to resolve GQs occurring in the nDNA. Human DNA2 localizes also in the mitochondria but its role in this organelle is still elusive. Notably, DNA2 was reported to be mutated in patients with autosomal-dominant progressive external ophthalmoplegia (adPEO), a condition characterized by the accumulation of multiple deletions in mtDNA.
The main goal of this project is to investigate the dynamic of G-quadruplexes formation in the mtDNA and the role of DNA2 in their resolution. This is a relevant question to understand whether GQs account for mtDNA deletions formation and accumulation in vivo.
The main goal of this project is to investigate the dynamic of G-quadruplexes formation in the mtDNA and the role of DNA2 in their resolution. This is a relevant question to understand whether GQs account for mtDNA deletions formation and accumulation in vivo.
"During the Marie Curie fellowship, I got involved in a project with the groups of Nasim Sabouri (Dept. of Medical Biochemistry and Biophysics) and Erik Chorell (Department of Chemistry) both at Umeå University, on the development of novel G-quadruplexes stabilizers that target specifically cancer cells. This project resulted in a publication in the Journal of American Chemical Society in 2020, in which I am enlisted as one of the first authors. Additionally,this work resulted in a patent and the creation of a company for exploiting these new compounds in the therapy against cancer.
Jamroskovic J*, Doimo M*, Chand K*, Obi I, Kumar R, Brännström K, Hedenström M, Das RN, Akhunzianov A, Deiana M, Kasho K, Sulis Sato S, Pourbozorgi PL, Mason JE, Medini P, Öhlund D, Wanrooij S#, Chorell E#, Sabouri N.# Quinazoline Ligands Induce Cancer Cell Death Through Selective STAT3 Inhibition and G-Quadruplex Stabilization. J Am Chem Soc,142 (6), 2876-2888 2020 Feb. * and # equal contributors
Press release for Jamroskovic, Doimo et al, : http://www.mynewsdesk.com/se/umea_universitet/pressreleases/ny-prototyp-foer-cancerlaekemedel-slaar-tvaa-flugor-i-en-smaell-2965648"
Jamroskovic J*, Doimo M*, Chand K*, Obi I, Kumar R, Brännström K, Hedenström M, Das RN, Akhunzianov A, Deiana M, Kasho K, Sulis Sato S, Pourbozorgi PL, Mason JE, Medini P, Öhlund D, Wanrooij S#, Chorell E#, Sabouri N.# Quinazoline Ligands Induce Cancer Cell Death Through Selective STAT3 Inhibition and G-Quadruplex Stabilization. J Am Chem Soc,142 (6), 2876-2888 2020 Feb. * and # equal contributors
Press release for Jamroskovic, Doimo et al, : http://www.mynewsdesk.com/se/umea_universitet/pressreleases/ny-prototyp-foer-cancerlaekemedel-slaar-tvaa-flugor-i-en-smaell-2965648"
In the work I recently published with the group of Nasim Sabouri and Erik Chorell, we have developed a novel class of compounds that act simultaneously on two independent well-recognize cancer targets, G-quadruplexes structures and the protein STAT3. This surprising finding opens new possibilities for the treatment of different types of cancers.